CN108276319B - A kind of thio-compounds and its application - Google Patents
A kind of thio-compounds and its application Download PDFInfo
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- CN108276319B CN108276319B CN201810156006.6A CN201810156006A CN108276319B CN 108276319 B CN108276319 B CN 108276319B CN 201810156006 A CN201810156006 A CN 201810156006A CN 108276319 B CN108276319 B CN 108276319B
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- C07C333/02—Monothiocarbamic acids; Derivatives thereof
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- C07C335/06—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to acyclic carbon atoms
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
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Abstract
The invention discloses a kind of novel thio-compounds, shown in general structure such as formula (I).Meanwhile the invention also discloses the novel thio-compounds to prepare the purposes in heavy metal destruction drug.Novel thio-compounds provided by the invention has the function of efficient heavy metal complexing, while having both the features such as stability is good and toxicity is low, the clinical medical value with good prospect.
Description
Technical field
The invention belongs to chemical drugs technical fields, and in particular to a kind of novel thio-compounds and its application.
Background technique
Health cost caused by the contact of occupational cadmium and Environmental Cadmium Pollution is the research hotspot of current Global Environmental Problems.
Long-term close contact cadmium and its compound can lead to the occupational chronic using kidney damage as main clinical manifestation in vocational activity
Cadmium poisoning, the whole world about 7% general population can due to cadmium environmental pollution suffering from chronic kidney trouble (see document, the duty such as Xia Lihua
Industry chronic cadium poisoning clinical conditions progress Chinese Professional medicine 2016,43 (1), 97-100).By Chronic Cadmium
" itai-itai " caused by poisoning regards as nuisance disease by Japanese government, which is mainly characterized by osteoporosis, skeleton pain, bone
Deformation (see document, easy ancestor tirelessly waits cadmium pollution and itai-itai occupation and health .2014,30 (17), 2511-2513).Cadmium poisoning
It is chronic process, it is 2~8 years that incubation period is most short, general 15~20 years.USA and EU has limited cadmium production and has used at present,
The toxicity committee, the U.S. is classified as the 6th noxious material for jeopardizing human health, can not only cause kidney, liver, testis equivalent damage,
It and is the determination carcinogenic substance (IA class) of international cancer research institute (IARC) announcement (see document: IARC.Monographs on
The evaluation of carcinogenic risks to humans.Lyon, France:International
Agency for Research on Cancer, 1993,58:41-117).
It is now recognized that the main mechanism of cadmium poisoning is, accumulated first in liver into intracorporal cadmium, inducing hepatocyte synthesis
Metallothionein, and generation cadmium metallothionein compound in combination is with blood circulation to kidney.Cadmium metallothionein is compound
Object is absorbed into S1 sections of proximal tubular and calm through glomerular filtration and renal tubule, be degraded under lysosome effect cadmium from
Son, cadmium ion cause transport protein function to change and mitochondrial respiratory failure, induced apoptosis in renal tubular cells by oxidative damage
(see document, first equal cadmium toxicity acts on interference method and its Recent Advances in Mechanism Chinese Professional medicine .2014,41 (2) to Li Guang,
222-226).China cadmium yield about 7000t/n is the use big country of cadmium and its compound, in Cd pollution control and cadmium poisoning
Prevention and treatment aspect still faces enormous challenge.
About the drug of prevention and treatment cadmium poisoning, specific drug is applied to clinic not yet both at home and abroad at present, and it is good to develop a kind of effect
The drive cadmium new drug low with toxicity has extremely important meaning.It the use of the cadmium accumulated in complexing agent drive row body is to prevent and treat cadmium poisoning most
One of effective measures.Currently used for treating cadmium poisoning complexing agent, mainly there are aminodithioformic acid class (DTC), ammonia carboxylic acids
(EDTA) and sulfydryl class complexing agent (BAL).Sulfydryl class complexing agent (BAL) such as Succimer and sodium dimercaptopropane sulfonate exist
In a short time can antagonism cadmium acute lethal effect, not can increase urine cadmium discharge；And to chronic cadium poisoning it is also invalid (see document,
The decorporation of horse east magnitude cadmium injury of kidney treats Chinese industrial medicine .1994,7 (6): 360-363).Ammonia carboxylic acids complexing agent
(EDTA) liver of MT of cadmium poisoning mouse organs and the excretion of kidney cadmium level, promotion cadmium can be reduced, such as calcium disodium edetate so as to antagonism cadmium
Acute Lethal Effects, but its may the reabsorption function to kidney have certain damage (see document, the edetic acid(EDTA) such as Chen Zhiqiang
The drive cadmium effect of calcium disodium and the influence medicine selected works to renal function, 2005,4 (3), 339-340).Dithiocarbamates first
Acids complexing agent (DTC) such as sodium diethyldithiocarbamate (DDTC) is (see document, AndensenO, Nidelsen
JB.Effects of diethytdithiocar-bamate on the toxicokinetics of c admium
Chloride in mice.Toxicol, 1989,552004-11-19:1-14)；Two sulphur of 4- methoxybenzyl-D- glucose amine-n-
For carboxylic acid sodium (M eOBGDTC), (see document, the such as Zhang Jiusong compound M eOBGDTC drives cadmium effect to sub- chronic cadium poisoning rat
The research Chinese Medical Sciences University journal .1996 of fruit, 25 (5) .476-478)；N- (2,3,4,5,6- penta hydroxy group hexyl)-N- (two
Bamic acid sodium base) half Guang of-L-threonine sodium and N- (2,3,4,5,6- penta hydroxy group hexyl)-N- (dithiocarbonic acid sodium base)-L-
Propylhomoserin sodium (see patent CN1137896A, Peng Shiqi etc., drives cadmium drug and its synthetic method and application)；With N- (2,3,4,5,6-
Penta hydroxy group hexyl)-N- (dithiocarbonic acid sodium base)-L- methionine sodium is (see patent CN1184260A, a kind ofization such as Tang little Jiang
Close object, its synthetic method and its application in standby heavy metal destruction and removing free radical drug), dithiocarbamates described above
Liver, kidney and blood of cadmium poisoning rat etc. may be effectively reduced through cell membrane and blood-brain barrier in formic acid class complexing agent (DTC)
The cadmium concentration of tissue, but the stability of aminodithioformic acid class complexing agent (DTC) is poor, in acid or weak alkaline aqueous solution item
It is all easier degradation under part and high temperature, super-humid conditions and releases carbon disulfide, nerve of the carbon disulfide to human or animal, painstaking effort
The systems such as pipe, reproduction, blood and breathing are toxic (see document, Li Shouqi etc., medical sci-tech data, 1974 (03) .102-
107；Fu Weizu, Shen Hong etc., labour medicine, 1998 (01) .18-21), therefore limit its application on drug.
Summary of the invention
Based on this, a kind of novel thioated is provided it is an object of the invention to overcome above-mentioned the deficiencies in the prior art place
Object is closed, has the function of efficient heavy metal complexing, while having both the features such as stability is good and toxicity is low.
To achieve the above object, the technical solution adopted by the present invention are as follows: a kind of novel thio-compounds, the new sulfur generation
Shown in the general structure of compound such as formula (I):
In formula, R1 is selected from unsubstituted or substituted monosaccharide groups or disaccharide base；
R2 is selected from formula (a), formula (b), formula (c), formula (d), formula (e), formula (f), formula (g), formula (h) or formula (i)；
In formula (a)~(i), X is selected from H, alkyl, alkenyl, alkynyl, naphthenic base, cycloalkenyl, heterocycle, heterocycloalkenyl, thick
Close cycloalkyl aryl, fused heteroarylcycloalkyl base, fused-aryl cycloalkenyl, condensed heteroaryl cycloalkenyl, fused-aryl heterocycle,
Condensed heteroaryl heterocycle, condensed heteroaryl heterocycloalkenyl, aryl, condensed cycloalkenylaryl, condenses fused-aryl heterocycloalkenyl
Cycloalkylaryl, annelated heterocycles base aryl, annelated heterocycles alkenyl aryl, heteroaryl, fused cycloalkyl heteroaryl, condensed cycloalkenyl
Heteroaryl, annelated heterocycles alkenyl heteroaryl, fused heterocyclylheteroaryl, aralkyl, heteroarylalkyl, aralkenyl, heteroaryl alkene
Base, sweet-smelling alkynyl, heteroaryl alkynyl, unsubstituted or substituted monosaccharide groups or disaccharide base；N is the integer of 0≤n≤16；
R3 is selected from H, NH4, metal ion, unsubstituted or substituted monosaccharide groups or disaccharide base, formula (b), formula (c), formula (g)；
R4 is selected from any side chain containing hydroxyl or sulphur atom, the ammonia of H, any aliphatic lateral chain of amino acid, amino acid
Any aryl side chains of base acid, any of amino acid containing amino, imidazole radicals, thienyl or guanidine radicals or contain S, O, N atom
Any side chain containing carboxyl or amide groups of the side chain of heterocycle, amino acid.
Preferably, the compound further includes its pharmaceutically acceptable derivates.
Preferably, the R1 is selected from unsubstituted or substituted xylosyl, fructosyl, glucosyl group, aralino, lactose
Base, sucrose base or malt-base.
Preferably, the R2 is selected from formula (a), formula (b) or formula (c), and n is 0 or 1；When n=0, X be selected from methyl, ethyl,
Propyl, isopropyl, isobutyl group, heptyl, cetyl or phenyl；When n=1, X is selected from 2- piperidyl, 2- tetrahydrofuran base, 2-
Nafoxidine base, 2- pyridyl group, 2- furyl, 2- thienyl or phenyl.
Preferably, the R3 is selected from H, NH4, Li, Na or K.
Preferably, the R4 is selected from cysteine side chain or methionine side chain.
Preferably, the novel thio-compounds is structure shown in formula (1)~(20):
It is highly preferred that the novel thio-compounds is structure shown in formula (2), (16) and (18).
Invention additionally provides the novel thio-compounds and its pharmaceutically acceptable derivates and drives away weight in preparation
Purposes in Metal Drugs.
Preferably, the heavy metal is cadmium and lead.
Novel thio-compounds and its pharmaceutically acceptable derivates provided by the invention can be used for preparing an expeling huge sum of money
The drug of category.
The preparation method of formula (I) compound of the present invention the following steps are included:
(1) water and sodium hydroxide is added in modus ponens (III) compound and formula (IV) compound, is warming up to 50-70 degree reaction 4-
8 hours；It is cooled to 15-35 degree, sodium borohydride is added portionwise, keeps the temperature 1-16 hours after adding, concentrated hydrochloric acid is added dropwise, adjusts pH=2-
3, it is cooled to 0-10 degree, keeps the temperature 2-24 hours, is filtered, is washed, it is dry, obtain formula (V) compound；
(2) formula (V) compound and triethylamine are added in THF, are stirred evenly, cooled to -10~10 degree, is added dropwise
Formula (VI) compound is warming up to 10-30 degree and keeps the temperature 1-3 hours, water is added, acid for adjusting pH=2-5 is added dropwise, is added after being added dropwise
Ethyl acetate extraction, separates organic layer, is washed with water, and concentration of organic layers obtains formula (VII) compound, and dehydrated alcohol dissolution is added,
Addition formula (VIII) compound, crystallization filter, washing, dry to get formula (I) compound.
Chemical equation is as follows:
Present inventor has found a kind of dithiocarbamates compound, general structure such as formula (II) early period
It is shown, shown in preferred structure such as formula (21).Its heavy metal destruction especially drives the effect of cadmium relative to existing dithiocarbamates
Formic acid class complexing agent (DTC) is more stable, and has the characteristics that effect is good and toxicity is low.Inventors have found that the application is novel
Thio-compounds can more efficiently be accumulated heavy metal destruction, simultaneously compared with the dithiocarbamates compound
The features such as stability is good and toxicity is low is had both, the clinical medical value with good prospect.
Compared with the existing technology, the invention has the benefit that novel thio-compounds provided by the invention has efficiently
Heavy metal function is complexed, can more efficiently accumulate heavy metal destruction, while have both the features such as stability is good and toxicity is low, tool
There is the clinical medical value of good prospect.
Unless otherwise indicated, the following term that the present invention uses is interpreted as following meanings:
Definition:
" alkyl " refers to the aliphatic hydrocarbyl with about 16 chain carbon atoms of about 1- of linear chain or branched chain.Preferred alkyl has
About 12 chain carbon atoms of 1-.Branch means one or more low alkyl groups, such as methyl, ethyl, propyl, with a straight chained alkyl phase
Even." low alkyl group " refers to the linear or branched alkyl group with about 6 chain carbon atoms of about 1-.Alkyl can be by one or more halogen
Element, naphthenic base or cycloalkenyl replace.Representative alkyl includes methyl, methyl fluoride, difluoromethyl, trifluoromethyl, cyclopropyl first
Base, cyclopentyl-methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, n-pentyl, 3- amyl, heptyl, octyl, nonyl,
Decyl and dodecyl.
Alkenyl " refers to the aliphatic hydrocarbyl of carbon-carbon double key, it can be linear chain or branched chain and containing about 2- about 15
A chain carbon atom.Preferred alkenyl contains about 12 chain carbon atoms of 2-；More preferable about 6 chain carbon atoms containing about 2-.Branch meaning
Refer to that one or more low alkyl groups are connected such as methyl, ethyl or propyl with a straight alkenyl." low-grade alkenyl " refers to about
The linear chain or branched chain alkenyl of about 4 chain carbon atoms of 2-.Alkenyl can be replaced by one or more halogens.Representative alkenyl
Including vinyl, acrylic, n-butene base, isobutenyl, 3- methyl but-2-ene base, n-pentene base, heptenyl, octenyl and
Dodecenyl succinic.
" alkynyl " refers to the aliphatic hydrocarbyl containing carbon-carbon triple bond, it can be linear chain or branched chain and containing about 2- about 15
Chain carbon atom.Preferred alkynyl about 12 chain carbon atoms containing 2-；More preferable about 4 chain carbon atoms containing about 2-.Branch means one
Or multiple low alkyl groups are connected such as methyl, ethyl or propyl with a straight-chain alkynyl." low-grade alkynyl " refers to about 4 chain carbon of about 2-
The linear chain or branched chain alkynyl of atom.Representative alkynyl includes acetenyl, propinyl, positive butynyl, 2- butynyl, 3- methyl fourth
Alkynyl, positive pentynyl, heptynyl, octynyl and dodecyne base.
" naphthenic base " refers to about 10 carbon atoms containing about 3-, the non-aromatic monocycle or more of about 10 carbon atoms of preferably from about 5-
Ring ring system.The ring of preferred naphthenic base contains about 6 annular atoms of about 5-.Naphthenic base can be arbitrarily by one or more identical or not
Same " ring system substituent " is (as defined herein) to be replaced.Representative monocyclic cycloalkyl includes cyclopenta, cyclohexyl, cycloheptyl
Base etc..Representative polycyclic naphthene base includes 1- naphthalane base, norborneol alkyl and adamantyl etc..
" cycloalkenyl " refers to about 10 carbon atoms containing about 3- containing at least one carbon-to-carbon double bond, preferably from about 5- about 10
The non-aromatic monocyclic of carbon atom or polycyclic ring system.Preferred cyclenes basic ring contains about 6 annular atoms of about 5-.Cycloalkenyl can be arbitrarily
By one or more identical or different " ring system substituents " substitution (as defined herein).Representative monocyclic cycloalkenyl includes
Cyclopentenyl, cyclohexenyl group, cycloheptenyl etc..Representative polycyclic ring alkenyl is norbornene.
" heterocycloalkenyl " refers to about a annular atom containing about 3-, the non-aromatic monocycle or more of about 10 annular atoms of preferably from about 5-
Ring ring system, one or more of annular atoms not instead of carbon atom, such as the element of nitrogen, oxygen or sulphur atom；And it contains
There are at least one carbon-to-carbon double bond or carbon-to-nitrogen double bond.Preferred heterocycloalkenyl contains about 6 annular atoms of about 5-.Before heterocycloalkenyl
Prefix aza, oxa- or thia refer respectively at least one nitrogen, oxygen or sulphur atom as annular atom.Heterocycloalkenyl can be any
Ground is by one or more ring system substituent substituent groups, wherein " ring system substituent " is as defined herein.The nitrogen or sulphur of heterocycloalkenyl
Atom can arbitrarily be oxidized to corresponding N- oxide, S- oxide or S, S- dioxide.Representative monocycle azacyclo-
Alkenyl include 1,2,3,4- tetrahydropyridines, 1,2- dihydropyridine base, Isosorbide-5-Nitrae-dihydropyridine base, 1,2,3,6- tetrahydropyridines, 1,
4,5,6- tetrahydropyrimidines, 2- pyrrolinyl, 3- pyrrolinyl, 2- imidazolinyl, 2- pyrazolinyl etc..Representative oxa- cyclenes
Base includes 3,4- dihydro -2H- pyrans, dihydrofuryl, fluoro dihydrofuryl etc..Representative polycyclic oxaheterocyclenyl groups are 7-
Oxabicyclo [2.2.1] heptenyl.Representative monocycle thia cycloalkenyl includes dihydrothiophene, dihydrogen phosphorothioate pyranose etc..
" heterocycle " refers to about 10 annular atoms containing about 3-, the non-aromatic saturation monocycle of about 10 annular atoms of preferably from about 5-
Or polycyclic ring system, one or more of annular atoms not instead of carbon atom, such as the element of nitrogen, oxygen or sulphur.It is preferred miscellaneous
Ring group contains about 6 annular atoms of about 5-.Prefix aza, oxa- or thia before heterocycle refer respectively at least one nitrogen, oxygen
Or sulphur atom is as annular atom.Heterocycle can be arbitrarily by one or more identical or different " ring system substituents " (as herein
Defined) replace.The nitrogen or sulphur atom of heterocycle can arbitrarily be oxidized to corresponding N- oxide, S- oxide or S, S- bis-
Oxide.Representative monocyclic heterocycles base includes piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thio-morpholinyl, thiazolidine
Base, 1,3-dioxolane base, Isosorbide-5-Nitrae-dioxane base, tetrahydrofuran base, tetrahydro-thienyl, tetrahydro thiapyran base etc..
" aryl " is about 14 carbon atoms of 6- containing finger, the aromatic monocyclic of about 10 carbon atoms of preferably from about 6- or polycyclic ring system.
Aryl can be arbitrarily replaced by one or more identical or different " ring system substituent " (as defined herein).It is representative
Aryl includes phenyl and naphthalene.
" heteroaryl " refers to about 14 annular atoms containing about 5-, the aromatic monocyclic or polycyclic ring of about 10 annular atoms of preferably from about 5-
System, one or more of annular atoms not instead of carbon atom, such as the element of nitrogen, oxygen or sulphur.Preferred heteroaryl contains
About 6 annular atoms of about 5-." heteroaryl " can be arbitrarily by one or more identical or different " ring system substituents " (such as this paper institute
Definition) replace.Prefix aza, oxa- or thia before heteroaryl mean at least one nitrogen, oxygen or sulphur atom as annular atom.
The nitrogen-atoms of heteroaryl can arbitrarily be oxidized to N- oxide.Representative heteroaryl includes pyrazinyl, furyl, thiophene
Base, pyridyl group, pyrimidine radicals, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrole radicals, pyrazolyl,
Triazolyl, 1,2,4- thia di azolies, pyrazinyl, pyridazinyl, quinoxalinyl, 2,3- phthalazinyl, imidazo [1,2-a] pyrrole
Pyridine, imidazo [2,1-b] thiazolyl, benzofuraxan base, indyl, azaindolyl, benzimidazolyl, benzothienyl, quinoline
Quinoline base, imidazole radicals, thienopyridine base, quinazolyl, Thienopyrimidine base, pyrrolopyridinyl, imidazopyridyl, isoquinoline
Quinoline base, benzo-aza indyl, 1,2,4- triazine radicals, benzothiazolyl etc..
" fused-aryl cycloalkenyl " refers to by condensed aryl and cycloalkenyl defined herein by removing cyclo-alkenyl moieties
Hydrogen atom derived from group.Preferred fused-aryl cycloalkenyl be those wherein aryl be phenyl and cycloalkenyl by about 5- about
The group of 6 annular atoms composition.Fused-aryl cycloalkenyl can arbitrarily be replaced by one or more ring system substituents, wherein " ring
It is substituent group " it is as defined herein.Representative fused-aryl cycloalkenyl includes 1,2- dihydronaphthalene and indenes etc., wherein by non-aromatic
Fragrant carbon atom is connected with parent fraction.
" condensed cycloalkenylaryl " refers to former by the hydrogen for removing aryl moiety by fused-aryl cycloalkenyl defined herein
Group derived from son.The representative condensed cycloalkenylaryl such as description to fused-aryl cycloalkenyl herein, the difference is that passing through
Aromatic carbon atom is connected with parent fraction.
" fused-aryl naphthenic base " refers to by condensed aryl and naphthenic base defined herein by removing cycloalkyl moiety
Hydrogen atom derived from group.Preferred fused-aryl naphthenic base be those wherein aryl be phenyl and naphthenic base by about 5- about
The group of 6 annular atoms composition.Fused-aryl naphthenic base can arbitrarily be replaced by one or more ring system substituents, wherein " ring
It is substituent group " it is as defined herein.Representative fused-aryl naphthenic base includes 1,2,3,4- tetralyls etc., wherein by non-
Aromatic carbon atom is connected with parent fraction.
" fused cycloalkylaryl ", which refers to, to be spread out by cycloalkyl aryl defined herein by removing the hydrogen atom of aryl moiety
Raw group.The representative fused cycloalkylaryl such as description to fused-aryl naphthenic base herein, the difference is that passing through aromatic carbon
Atom is connected with parent fraction.
" fused-aryl heterocycloalkenyl " refers to by condensed aryl and heterocycloalkenyl defined herein by removing heterocycle alkene
Group derived from the hydrogen atom of base portion point.Preferred fused-aryl heterocycloalkenyl be those wherein aryl is phenyl and heterocycle alkene
The group that base is made of about 6 annular atoms of about 5-.Prefix aza, oxa- before the heterocycloalkenyl part of fused-aryl heterocycloalkenyl
Or thia refers respectively at least one nitrogen, oxygen or sulphur atom as annular atom.Fused-aryl heterocycloalkenyl can be arbitrarily by one
A or multiple ring system substituent substituent groups, wherein " ring system substituent " is as defined herein.The heterocycle of fused-aryl heterocycloalkenyl
The nitrogen or sulphur atom of alkenyl part can arbitrarily be oxidized to corresponding N- oxide, S- oxide or S, S- dioxide.Generation
The fused-aryl heterocycloalkenyl of table includes 3H- indolinyl, 1H-2- oxo-quinolyl, 2H-1- oxo isoquinolyl, 1,
2- dihydroquinoline base, 3,4- dihydroquinoline base, 1,2- dihydro-isoquinoline base and 3,4- dihydro-isoquinoline base etc., wherein by non-
Aromatic carbon atom is connected with parent fraction.
" annelated heterocycles alkenyl aryl " refers to by fused-aryl heterocycloalkenyl defined herein by removing aryl moiety
Group derived from hydrogen atom.Such as description to fused-aryl heterocycloalkenyl herein of representative annelated heterocycles alkenyl aryl, it is different
It is to be connected by aromatic carbon atom with parent fraction.
" fused-aryl heterocycle " refers to by condensed aryl and heterocycle defined herein by removing heterocyclyl moieties
Hydrogen atom derived from group.Preferred fused-aryl heterocycle be those wherein aryl be phenyl and heterocycle by about 5- about
The group of 6 annular atoms composition.Prefix aza, oxa- or thia before heterocycle refer respectively at least one nitrogen, oxygen or sulphur
Atom is as annular atom.Fused-aryl heterocycle can be arbitrarily by one or more ring system substituent substituent groups, wherein " ring system takes
Dai Ji " is as defined herein.The nitrogen or sulphur atom of the heterocyclyl moieties of fused-aryl heterocycle can be arbitrarily oxidized to accordingly
N- oxide, S- oxide or S, S- dioxide.Representative preferred fused-aryl heterocyclic ring system includes adjacent benzene
Dicarboximide, Isosorbide-5-Nitrae-benzo dioxane, indolinyl, 1,2,3,4- tetrahydroisoquinolines, 1,2,3,4- tetrahydro quinolines
Quinoline, 1H-2,3- dihydro-iso indolyl, 2,3- dihydrobenzo [f] isoindolyl, 1,2,3,4- tetrahydro benzo [g] isoquinolyls etc.,
Wherein it is connected by non-aromatic carbon atom with parent fraction.
" annelated heterocycles base aryl " refers to the hydrogen by fused-aryl heterocycle defined herein by removing heterocyclyl moieties
Group derived from atom.Description of the representative preferred annelated heterocycles base aryl loop system such as to fused-aryl heterocycle, no
Same is to be connected by aromatic carbon atom with parent fraction.
" condensed heteroaryl cycloalkenyl " refers to by condensed heteroaryl and cycloalkenyl defined herein by removing cycloalkenyl
Group derived from partial hydrogen atom.Preferred condensed heteroaryl cycloalkenyl be those wherein heteroaryl and cycloalkenyl respectively contain about 5-
The group of about 6 annular atoms.It is former that prefix aza, oxa- or thia before heteroaryl refer respectively at least one nitrogen, oxygen or sulphur
Son is used as annular atom.Condensed heteroaryl cycloalkenyl can be arbitrarily by one or more ring system substituent substituent groups, wherein " ring system takes
Dai Ji " is as defined herein.The nitrogen of the heteroaryl moieties of condensed heteroaryl cycloalkenyl can arbitrarily be oxidized to corresponding N- oxygen
Compound.Representative condensed heteroaryl cycloalkenyl includes 5,6- dihydroquinoline base, 5,6- dihydro-isoquinoline base, 5,6- dihydro quinoline
Quinoline base, 5,6- dihydroquinazoline base, 4,5- dihydro -1H- benzimidazolyl and 4,5- dihydrobenzo oxazolyl etc., wherein passing through
Non-aromatic carbon atom is connected with parent fraction.
" fused rings alkenyl heteroaryl " refers to by condensed heteroaryl cycloalkenyl defined herein by removing heteroaryl moieties
Hydrogen atom derived from group.Description of the representative fused rings alkenyl heteroaryl such as to condensed heteroaryl cycloalkenyl, it is different
It is to be connected by aromatic carbon atom with parent fraction.
" fused heteroarylcycloalkyl base " refers to by condensed heteroaryl and naphthenic base defined herein by removing naphthenic base
Group derived from partial hydrogen atom.Preferred fused heteroarylcycloalkyl base is those wherein heteroaryl about 6 ring originals containing about 5-
The group of son and naphthenic base also about 6 annular atoms containing about 5-.Prefix aza, oxa- or thia before heteroaryl refer respectively to
A rare nitrogen, oxygen or sulphur atom are as annular atom.Fused heteroarylcycloalkyl base can arbitrarily be replaced by one or more ring systems
Base substituent group, wherein " ring system substituent " is as defined herein.The nitrogen of the heteroaryl moieties of fused heteroarylcycloalkyl base can be any
Ground is oxidized to corresponding N- oxide.Representative fused heteroarylcycloalkyl base includes 5,6,7,8- tetrahydric quinoline groups, 5,6,
7,8- tetrahydro isoquinolyls, 5,6,7,8- tetrahydroquinoxaline bases, 5,6,7,8- tetrahydro quinazoline bases, 4,5,6,7- tetrahydro -1H- benzene
And imidazole radicals, 4,5,6,7- tetrahydro benzo oxazolyls, 1H-4- oxa- -1,5- benzodiazine -2- ketone group (onyl) and 1,3- bis-
Hydrogen imidazoles-[4,5]-pyridin-2-ones base (onyl), wherein being connected by non-aromatic carbon atom with parent fraction.
" fused cycloalkyl heteroaryl " refers to by condensed Heteroarylcycloalkyl defined herein by removing heteroaryl moiety
Group derived from the hydrogen atom divided.Such as description to fused heteroarylcycloalkyl base herein of representative fused cycloalkyl heteroaryl,
The difference is that being connected by aromatic carbon atom with parent fraction.
" condensed heteroaryl heterocycloalkenyl ", which refers to, to be passed through by condensed heteroaryl and heterocycloalkenyl defined herein except impurity elimination
Group derived from the hydrogen atom of cyclo-alkenyl moieties.Preferred condensed heteroaryl heterocycloalkenyl be those wherein heteroaryl containing about 5- about
The group of 6 annular atoms and heterocycloalkenyl also about 6 annular atoms containing about 5-.Prefix aza before heteroaryl or heterocycloalkenyl,
Oxa- or thia refer respectively at least one nitrogen, oxygen or sulphur atom as annular atom.Condensed heteroaryl heterocycloalkenyl can be any
Ground is by one or more ring system substituent substituent groups, wherein " ring system substituent " is as defined herein.Condensed heteroaryl heterocycle alkene
The nitrogen of the heteroaryl moieties of base can arbitrarily be oxidized to corresponding N- oxide.The heterocycloalkenyl of condensed heteroaryl heterocycloalkenyl
Partial nitrogen or sulphur atom can arbitrarily be oxidized to N- oxide, S- oxide or S, S- dioxide.It is representative condensed
Heteroaryl heterocycloalkenyl includes 7,8- dihydro [1,7] phthalazinyl, 1,2- dihydro [2,7] phthalazinyl 6,7- dihydro-
3H- imidazo [4,5-c] pyridyl group, 1,2- dihydro -1,5- phthalazinyl, 1,2- dihydro -1,6- phthalazinyl, 1,2-
Dihydro -1,7- phthalazinyl, 1,2- dihydro -1,8- phthalazinyl, 1,2- dihydro -2,6- phthalazinyl etc., wherein leading to
Non-aromatic carbon atom is crossed to be connected with parent fraction.
" annelated heterocycles alkenyl heteroaryl " refers to by condensed heteroaryl heterocycloalkenyl defined herein by removing heteroaryl
Group derived from partial hydrogen atom.Representative annelated heterocycles alkenyl heteroaryl is as herein to condensed heteroaryl heterocycloalkenyl
Description, the difference is that being connected by aromatic carbon atom with parent fraction.
" condensed heteroaryl heterocycle " refers to by condensed heteroaryl and heterocycle defined herein by removing heterocycle
Group derived from partial hydrogen atom.Preferred condensed heteroaryl heterocycle is those wherein heteroaryl about 6 ring originals containing about 5-
The group of son and heterocycle also about 6 annular atoms containing about 5-.Prefix aza, oxa- or thia point before heteroaryl or heterocycle
Do not refer at least one nitrogen, oxygen or sulphur atom as annular atom.Condensed heteroaryl heterocycle can be arbitrarily one or more
Ring system substituent substituent group, wherein " ring system substituent " is as defined herein.The heteroaryl moieties of condensed heteroaryl heterocycle
Nitrogen can arbitrarily be oxidized to corresponding N- oxide.The nitrogen or sulphur atom of the heterocyclyl moieties of condensed heteroaryl heterocycle can
Arbitrarily it is oxidized to N- oxide, S- oxide or S, S- dioxide.Representative condensed heteroaryl heterocycle includes 2,
3- dihydro -1H pyrroles [3,4-b] quinoline -2- base, 1,2,3,4- tetrahydro benzo [b] [1,7] benzodiazine -2- bases, 1,2,3,4-
Tetrahydro benzo [b] [1,6] benzodiazine -2- base, 1,2,3,4- tetrahydro -9H- pyrido [3,4-b] indoles -2- bases, 1,2,3,
4- tetrahydro -9H- pyrido [4,3-b] indoles -2- base, 2,3- dihydro -1H- pyrrolo- [3,4-b] indoles -2- base, 1H-2,3,4,
5- tetrahydroazepine simultaneously [3,4-b] indoles -2- base, 1H-2,3,4,5- tetrahydroazepines simultaneously [4,3-b] indol-3-yl, 1H-2,
3,4,5- tetrahydroazepines simultaneously [4,5-b] indoles -2- base, 5,6,7,8- tetrahydro [1,7] phthalazinyls, 1,2,3,4- tetrahydros
Simultaneously [2,3-b] pyridyl group, 2,3- dihydro [Isosorbide-5-Nitrae] dioxa English is simultaneously for [2,7] phthalazinyl, 2,3- dihydro [Isosorbide-5-Nitrae] dioxa English
[2,3-b] pyridyl group, 3,4- dihydro -2H-1- oxa- [4,6] phthalazinyl, 4,5,6,7- tetrahydro -3H- imidazos [4,5-
C] pyridyl group, 6,7- dihydro [5,8] phthalazinyl, 1,2,3,4- tetrahydro [1,5] phthalazinyls, 1,2,3,4- tetrahydros [1,
6] phthalazinyl, 1,2,3,4- tetrahydros [1,7] phthalazinyl, 1,2,3,4- tetrahydro [1,8] phthalazinyls, 1,2,3,
4- tetrahydro [2,6] phthalazinyl etc., wherein being connected by non-aromatic carbon atom with parent fraction.
" fused heterocyclylheteroaryl " refers to by condensed heteroaryl heterocycle defined herein by removing heteroaryl moieties
Hydrogen atom derived from group.Such as description to condensed heteroaryl heterocycle herein of representative fused heterocyclylheteroaryl, no
Same is to be connected by aromatic carbon atom with parent fraction.
" aralkyl " refers to wherein aryl and alkyl is foregoing aryl-alkyl group.Preferred aralkyl is containing low
Grade alkyl.Representative aralkyl includes benzyl, 2- phenethyl and menaphthyl.
" aralkenyl " refers to wherein aryl and alkenyl is foregoing aryl-kiki alkenyl group.Preferred virtue chain
Alkenyl contains low-grade alkenyl.Representative aralkenyl includes 2- styryl and 2- naphthalene vinyl.
" sweet-smelling alkynyl " refers to wherein aryl and alkynyl is foregoing aryl-alkynyl group.Preferred sweet-smelling alkynyl contains
Low-grade alkynyl.Representative sweet-smelling alkynyl includes phenylacetylene base and naphthalene acetenyl.
" heteroarylalkyl " refers to wherein heteroaryl and alkyl is foregoing heteroaryl-alkyl-group.Preferred heteroaryl
Alkyl contains low alkyl group.Representative heteroarylalkyl includes picolyl, 2- (furans -3- base) ethyl and quinoline -3- Ji Jia
Base.
" heteroaralkenyl " refers to wherein heteroaryl and alkenyl is foregoing heteroaryl-alkenyl-group.It is preferred that
Heteroaralkenyl contain low-grade alkenyl.Representative heteroaralkenyl includes 2- (pyridin-3-yl) vinyl and 2- (quinoline
Quinoline -3- base) vinyl.
" heteroaryl alkynyl " refers to wherein heteroaryl and alkynyl is foregoing heteroaryl-alkynyl group.Preferred heteroaryl
Alkynyl contains low-grade alkynyl.Representative heteroaryl alkynyl includes pyridin-3-yl acetenyl and quinoline -3- ethyl-acetylene base.
" monosaccharide groups " refer to polyhydroxy aldehyde or polyhydroxyketone group containing 3-9 carbon atom.Preferred monosaccharide groups are fruit
Glycosyl, xylosyl, glucosyl group.
" disaccharide base ", which refers to, removes the polyhydroxy that a hydrone forms glycosidic bond through condensation reaction by two monosaccharide molecules
Aldehyde or polyhydroxyketone group.Preferred disaccharide base is lactose base, malt-base, sucrose base.
Specific embodiment
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiment to the present invention
It is described further.
Embodiment 1
Novel thio-compounds shown in formula (2): 2- [(ethoxy thiocarbonyl) (2,3,4,5,6- penta hydroxy group hexyl)
Amino] -4- methylmercapto butyric acid sodium preparation
(1) preparation of 2- (2,3,4,5,6- penta hydroxy group hexyl) amino -4- methylmercapto butyric acid
Methionine (100g, 0.67mol) is added in 2L reaction flask, glucose (121g, 0.67mol) is added water (1L), stirs
It mixes and sodium hydroxide (26.8g, 0.67mol) is added, be warming up to 60 degree and react 6 hours, be cooled to 25 degree, sodium borohydride is added portionwise
(25.3g, 0.67mol) is added for 2 hours, and 25 degree keep the temperature 16 hours, and 35% hydrochloric acid (139.7g, 1.34mol) is added dropwise and adjusts reaction mixed
Object pH=2-3 is closed, 0 degree is cooled to and keeps the temperature 2 hours, filter, wash, it is dry, obtain 2- (2,3,4,5,6- penta hydroxy group hexyl) amino-
4- methylmercapto butyric acid (126g, 0.40mol), off-white powder, HPLC purity 98.0%, yield 60%；
(2) novel thio-compounds shown in formula (2): 2- [(ethoxy thiocarbonyl) (2,3,4,5,6- penta hydroxy group hexyl) ammonia
Base] -4- methylmercapto butyric acid sodium preparation
A, 2- (2,3,4,5,6- penta hydroxy group hexyl) amino -4- methylmercapto butyric acid is added into 500ml reaction flask
(31.5g, 0.10mol), triethylamine (22.3g, 0.22mol), THF (160ml) cool to 0-10 degree, thio chloro-carbonic acid are added dropwise
Ethyl ester (12.4g, 0.10mol)；
B, it drips, then is warming up to 30 degree and keeps the temperature 2 hours, be added water (125ml), 35% hydrochloric acid of dropwise addition (12.5g,
PH=2-5 0.12mol) is adjusted, ethyl acetate (160ml) extraction is added, separates organic layer, is washed with water (125ml), concentration steams
Solvent adds dehydrated alcohol (125ml) dissolution, is added sodium hydroxide (4g, 0.10mol), and 30 degree keep the temperature 1 hour, filtering,
Washing, dry compound (2) 2- [(ethoxy thiocarbonyl) (2,3,4,5,6- penta hydroxy group hexyl) amino] -4- methylmercapto butyric acid
Sodium (16.2g, 0.0382mol), off-white powder, HPLC purity 98.8%, yield 38.2%.
1HNMR (400MHz, D2O) δ 4.47-4.71 (m, 1H), 4.21-4.40 (m, 2H), 3.64-3.83 (m, 6H),
3.52-3.60 (m, 2H), 2.67-2.68 (m, 2H), 2.38-2.42 (m, 2H), 2.14 (s, 3H), 1.28-1.32 (m, 3H)；
ESI-MS(m/z):400.1。
Embodiment 2
Novel thio-compounds shown in formula (16): 2- [(dimethylamine thiocarbonyl) (and 2,3,4,5,6- penta hydroxy group oneself
Base) amino] -4- methylmercapto butyric acid sodium preparation
A, 2- (2,3,4,5,6- penta hydroxy group hexyl) amino -4- methyl mercapto fourth is prepared by same 1 the method for embodiment
Acid, into 500ml reaction flask be added 2- (2,3,4,5,6- penta hydroxy group hexyl) amino -4- methylmercapto butyric acid (31.5g,
0.10mol), triethylamine (22.3g, 0.22mol), THF (160ml) cool to -10~0 degree, and the thio formyl of dimethylamino is added dropwise
Chlorine (12.4g, 0.10mol)；
B, it drips, then is warming up to -10~0 degree and keeps the temperature 2 hours, be added water (125ml), 35% hydrochloric acid of dropwise addition (12.5g,
PH=2-5 0.12mol) is adjusted, ethyl acetate (160ml) extraction is added, separates organic layer, is washed with water (125ml), concentration is steamed
Solvent out adds dehydrated alcohol (125ml) dissolution, is added sodium hydroxide (4g, 0.10mol), and 30 degree keep the temperature 1 hour, mistake
Filter, washing, dry compound (16) 2- [(dimethylamine thiocarbonyl) (2,3,4,5,6- penta hydroxy group hexyl) amino] -4- first
Sulfenyl sodium butyrate (15.9g, 0.0376mol), off-white powder, HPLC purity 98.5%, yield 37.6%.
1HNMR (400MHz, D2O) δ 4.42-4.68 (m, 1H), 3.62-3.80 (m, 6H), 3.50-3.57 (m, 2H),
2.64-2.65 (m, 2H), 2.53-2.56 (m, 6H), 2.35-2.40 (m, 2H), 2.12 (s, 3H)； ESI-MS(m/z):
399.5。
Embodiment 3
Novel thio-compounds shown in formula (18): 2- [(ethylenebis dithiocarbamate carbonyl) (and 2,3,4,5,6- penta hydroxy group oneself
Base) amino] -4- methylmercapto butyric acid sodium preparation
A, 2- (2,3,4,5,6- penta hydroxy group hexyl) amino -4- methyl mercapto fourth is prepared by same 1 the method for embodiment
Acid, into 500ml reaction flask be added 2- (2,3,4,5,6- penta hydroxy group hexyl) amino -4- methylmercapto butyric acid (31.5g,
0.10mol), triethylamine (22.3g, 0.22mol), THF (160ml), cool to 0-10 degree, be added dropwise thio propionyl chloride (10.9g,
0.10mol)；
B, it drips, then is warming up to 30 degree and keeps the temperature 2 hours, be added water (125ml), 35% hydrochloric acid of dropwise addition (12.5g,
PH=2-5 0.12mol) is adjusted, ethyl acetate (160ml) extraction is added, separates organic layer, is washed with water (125ml), concentration is steamed
Solvent out adds dehydrated alcohol (125ml) dissolution, is added sodium hydroxide (4g, 0.10mol), and 30 degree keep the temperature 1 hour, mistake
Filter, washing, dry compound (18) 2- [(ethylenebis dithiocarbamate carbonyl) (2,3,4,5,6- penta hydroxy group hexyl) amino] -4- first sulphur
Base sodium butyrate (16.9g, 0.0415mol), off-white powder, HPLC purity 98.9%, yield 41.5%.
1HNMR (400MHz, D2O) δ 4.38-4.62 (m, 1H), 3.63-3.78 (m, 6H), 3.53-3.62 (m, 2H),
2.78-2.81 (m, 2H), 2.63-2.66 (m, 2H), 2.36-2.42 (m, 2H), 2.08 (s, 3H), 1.31-1.34 (m, 3H)；
ESI-MS(m/z):384.5。
Embodiment 4
The preparation method of novel thio-compounds shown in formula (1), (3)~(15), (17) and (19)~(20) is removed
Be added in step A into 500ml reaction flask 2- (2,3,4,5,6- penta hydroxy group hexyl) amino -4- methylmercapto butyric acid (31.5g,
0.10mol), triethylamine (22.3g, 0.22mol), THF (160ml), after cooling to 0-10 degree, the reaction raw materials and formula of dropwise addition
(2) novel thio-compounds shown in (16) and (18) is different outer, other reaction conditions are all the same, in each preparation of compounds
The raw material that step A is added dropwise is as shown in table 1:
The selection of 1 raw material of table
Embodiment 5
The present embodiment studies the effect that novel thio-compounds shown in formula (2), (16) and (18) drives away cadmium.
The present embodiment studies expeling cadmium using the treatment MT of cadmium poisoning mouse organs experiment of compound shown in formula (2), (16) and (18)
Effect, while the dithiocarbamates compound of structure shown in formula (21) is set as a control group.Shown in formula (21)
The dithiocarbamates compound of structure, (two is thio by-N- for the entitled N- (2,3,4,5,6- penta hydroxy group hexyl) of chemistry
Group-4 ethyl formate)-l-methionine sodium, it is prepared by following methods: 2- (2,3,4,5,6- five is added in 500ml reaction flask
Hydroxyl hexyl) amino -4- methylmercapto butyric acid (31.5g, 0.10mol) is dissolved in 100ml water, the ammonium hydroxide of 25% concentration is added
(27.4g, 0.40mol) is cooled to 5 degree, and lower carbon disulfide (30.4g, 0.40mol) of nitrogen protection is dissolved in Isosorbide-5-Nitrae-dioxane
It in (30 ml), is slowly added dropwise into, heat preservation 5-10 degree reacts 15 hours.After be added methylene chloride (60ml) extraction, point
Falling organic layer, water layer is cooled to 5-10 degree, and the sodium hydrate aqueous solution (18.8g, 0.20mol) that 40% concentration is added dropwise is entered, then
Bromoethane (21.9g, 0.20mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (30ml), is slowly added dropwise into, heat preservation 5-10 degree reaction
15 hours.After methylene chloride (60ml) extraction is added, point fall organic layer, water layer is spin-dried for, and 90ml methanol is added in obtained solid
To enter, inorganic salts solid is precipitated, filtering, mother liquor concentrations are dry, and dehydrated alcohol mashing is added, and 30 degree keep the temperature 1 hour, it filters, washing,
Dry compound (21) 2- [(ethylenebis dithiocarbamate carbonyl) (2,3,4,5,6- penta hydroxy group hexyl) amino] -4- methylmercapto butyric acid sodium
(17.6g, 0.04mol), off-white powder, HPLC purity 98%, yield 40%.11HNMR (400MHz, D2O) δ 4.36 (m,
1H), 3.65-3.73 (m, 6H), 3.52-3.56 (m, 2H), 2.20-2.24 (m, 2H), 2.15-2.18 (m, 2H), 2.03 (s,
3H), 1.18-1.22 (m, 2H), 1.04-1.06 (m, 3H)； ESI-MS(m/z):416.5.
(1) experimental method
(1) preparation of 0.2mg/ml (1.1 μm of ol/ml) cadmium chloride solution: 24.9mg (0.11mmol) caddy half is weighed
(pentahydrate), 170.7mg (2.2mmol) mercaptoethanol add physiological saline to 100ml, and dissolution mixes, and 4 degree of ice are placed in sealing
Case saves.
(2) preparation of compound (2), (16), (18) and (21) medical fluid:
1. 63.5mg/ml (0.15mmol/ml) compound (2) solution is prepared, 6.35g (15mmol) compound (2) is weighed,
Add physiological saline to 100ml, dissolution mixes, sealing, places 4 degree of refrigerators and saves；
2. 63.4mg/ml (0.15mmol/ml) compound (16) solution is prepared, 6.34g (15mmol) compound is weighed
(16), add physiological saline to 100ml, dissolution mixes, sealing, places 4 degree of refrigerators and saves；
3. 61.1mg/ml (0.15mmol/ml) compound (18) solution is prepared, 6.11g (1.5mmol) compound is weighed
(18), add physiological saline to 100ml, dissolution mixes, sealing, places 4 degree of refrigerators and saves；
4. 65.7mg/ml (0.15mmol/ml) compound (21) solution is prepared, 6.57g (15mmol) compound is weighed
(21), add physiological saline to 100ml, dissolution mixes, sealing, places 4 degree of refrigerators and saves；
(3) mouse cadmium poisoning model manufacturing: choosing health KM male mice 30 is divided into blank control group 5, model group 25
Only.Blank control group is according to 10ml/kg weight intraperitoneal injection of saline, and continuous 4 days.Model group is according to 10ml/kg weight abdomen
0.2mg/ml (1.1 μm of ol/ml) cadmium chloride solution described in chamber injection (1), continuous 4 days；Then, model group mouse by weight with
Machine is distributed as model control group, compound (2) treatment group, compound (16) treatment group, compound (18) treatment group and compound
(21) treatment group, every group each 5.
(4) MT of cadmium poisoning mouse organs dosage regimen: blank control group in the mouse cadmium poisoning model that above-mentioned steps (3) obtain is treated
Physiological saline 0.9%NS is given with the oral stomach-filling of model control group；Compound (2), (16), (18) and (21) treatment group is equal
The respective solution of above-mentioned (2) the configured same molar ratio (0.15mmol/ml) of oral stomach-filling；Each group presses 10ml/Kg body
The oral gastric infusion of weight, 1 times/day, successive administration 4 days, see Table 2 for details:
Table 2 treats MT of cadmium poisoning mouse organs dosage regimen
(5) acquisition for the treatment of MT of cadmium poisoning mouse organs tissue sample, pretreatment and Indexs measure: 1. blood specimen collection: MT of cadmium poisoning mouse organs
After drug therapy, acquire anticoagulation about 1m L (heparin sodium is anticoagulant).Collecting sample is saved in refrigerator freezing.2. liver and kidney
Tissue samples acquisition: after mouse blood sampling, all dissections is put to death, liver and kidney are taken.Remove fat, the knot of liver and renal tissue surface
After forming tissue and coating, blood stains are washed away with physiological saline, and suck moisture with clean filter paper.Liver and kidney are weighed.After weighing,
It is saved loaded on cryopreservation tube in refrigerator freezing.3. liver and kidney pretreatment: freezing liver and kidney samples A are taken out holding chamber from refrigerator
Temperature thaw after, be respectively put into the small beaker of 50ml, be added 2.5ml excellent pure grade concentrated nitric acid, 1.0ml excellent pure grade hydrogen peroxide and
0.25ml excellent pure grade perchloric acid is covered overnight with surface plate.Then 180 DEG C of high temperature digestion to white cigarettes emit to the greatest extent on electric hot plate, liquid
Body volatilizes, and only when surplus solid, after rinsing surface plate with deionized water, makes dissolution of crystals.Liquid in beaker is evaporated, placement is removed
After room temperature, repeatedly washes beaker on a small quantity with deionized water and be transferred in 10m colorimetric cylinder.4. sample Indexs measure: blood sample and pretreatment
Liver and kidney samples A using inductively coupled plasma mass spectrometry ICP-MS detect cadmium content.
(2) experimental result
Experimental data is indicated with mean ± standard deviation, carries out variance analysis using SPSS17.0 software, P < 0.05 indicates system
Meter learns significant difference, and particular exam the results are shown in Table 3:
3 compound of table treats the variation of MT of cadmium poisoning mouse organs tissue sample cadmium content
Note: △ indicates to compare P < 0.05 with blank control group；▲ indicate to compare P < 0.05 with model control group；■ indicate with
Compound (21) treatment group compares P < 0.05.
From the above results, cadmium drives relative to model control group blood in compound treatment group shown in formula (2), (16) and (18)
45% or more rate (P < 0.05), and cadmium rate statistically-significant difference P < 0.05 is driven relative to compound (21) treatment group's blood；Chemical combination
Object (2), (16) and (18) treatment group drive cadmium rate relative to model control group kidney and reach 30 or more % (P < 0.05), and relative to
Compound (21) treatment group's kidney cadmium drives cadmium rate statistically-significant difference P < 0.05；Compound (2), (16) and (18) treatment group is opposite
Cadmium rate is driven in model control group liver to reach 50 or more % (P < 0.05), and drives cadmium rate system relative to compound (21) treatment group liver
Meter learns significant difference P < 0.05.Illustrate that the novel thio-compounds (2), (16) and (18) of the present invention drives away the effect of cadmium better than chemical combination
Object (21).The effect and formula (2) of the expeling cadmium of compound shown in formula (1), (3)~(15), (17) and (19)~(20),
(16) and compounds shown in (18) seemingly, effect is omitted better than compound shown in formula (21), specific data.
Embodiment 6
Novel thio-compounds shown in the present embodiment Research-type (2), (16) and (18) is to acute toxicity test in mice.
It is 600mg/ml solution that compound shown in formula (2), (16) and (18), which prepares 10ml concentration,；Select health KM male small
Mouse 15, mouse is compound (2), (16) and (18) group by weight random distribution；Each group mouse is primary by 10mL/Kg weight
Property oral stomach-filling to give concentration be each compound solution of 600mg/ml.Poisoning manifestations, the death of toy are observed after contamination daily
Situation is observed continuously 14 days, and concrete outcome is shown in Table 4.
4 compound acute toxicity test of table
The above results show: experimental animal is showed no abnormal response, and Normal-weight increases, and has no animal dead, dissects meat
Eye observation has no liver and renal lesions.By WHO acute toxicity grading criteria, compound (2), (16) and (18) LD50 is greater than
5000mg/kg belongs to minimum micro- malicious grade.
Embodiment 7
The stability of novel thio-compounds shown in the present embodiment Research-type (2), (16) and (18).
Stability analysis is carried out to compound same concentrations solution shown in formula (2), (16) and (18) and solid, the results are shown in Table
5 and 6:
5 compound solution stability analysis of table
6 compound solid stability analysis of table
The above results show that compound shown in formula (2), (16) and (18) is stable, and have no and decompose noxious material curing
Carbon CS2.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range is protected, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should
Understand, it can be with modification or equivalent replacement of the technical solution of the present invention are made, without departing from the essence of technical solution of the present invention
And range.
Claims (3)
1. a kind of thio-compounds, which is characterized in that the thio-compounds is selected from:
2. thio-compounds according to claim 1 is preparing the purposes in heavy metal destruction drug.
3. purposes according to claim 2, which is characterized in that the heavy metal is cadmium and lead.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1137896A (en) * | 1995-06-13 | 1996-12-18 | 北京医科大学 | Anti-cadmium medicines and their synthesis and medical application |
| CN1343493A (en) * | 2001-09-29 | 2002-04-10 | 北京艾叶医药技术有限公司 | Application of N-gluco-N-bithiocarboxylic acid-L-amino acid sodium in repelling Pt |
| CN1884260A (en) * | 2005-06-22 | 2006-12-27 | 广东省职业病防治院 | A compound, its synthesis method, and its use in preparation of medicament with heavy metal destruction and free radical removal |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1137896A (en) * | 1995-06-13 | 1996-12-18 | 北京医科大学 | Anti-cadmium medicines and their synthesis and medical application |
| CN1343493A (en) * | 2001-09-29 | 2002-04-10 | 北京艾叶医药技术有限公司 | Application of N-gluco-N-bithiocarboxylic acid-L-amino acid sodium in repelling Pt |
| CN1884260A (en) * | 2005-06-22 | 2006-12-27 | 广东省职业病防治院 | A compound, its synthesis method, and its use in preparation of medicament with heavy metal destruction and free radical removal |
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